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Synthesis 2010(24): 4287-4299  
DOI: 10.1055/s-0030-1258967
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

Novel, Versatile Three-Step Synthesis of 1,2,3,4,10,10a-Hexahydro­pyrazino[1,2-a]indoles by Intramolecular Carbene-Mediated C-H Insertion

Niels Krogsgaard-Larsena, Mikael Begtrupa, Matthias M. Hertha, Jan Kehler*b
a Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen, 2 Universitetsparken, 2100 Copenhagen, Denmark
b H. Lundbeck A/S, Department of Medicinal Chemistry, 9 Ottiliavej, 2500 Valby, Denmark
Fax: +45 36438237; e-Mail: jke@lundbeck.com;
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Publication History

Received 31 August 2010
Publication Date:
09 November 2010 (online)

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Abstract

A new convenient three-step synthesis of the privileged CNS scaffold 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles has been developed. The method makes use of an intramolecular carbene-mediated C-H insertion in phenylpiperazine-derived tosyl­hydrazones made from 2-fluorobenzaldehydes. Notably, the piperazine can be replaced with other cyclic nitrogen bases and the methodology is successfully extended to pyrrolidine, piperidine, azepane, morpholine, and homopiperazine.

Key words

1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles - C-H insertion - phenylpiperazine - carbene - cyclization

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